With over 450,000 surgeries performed annually in the US alone, total knee replacement (TKR) has become a common surgical procedure to alleviate pain and increase functional mobility in diseased or traumatized knee joints. A major limiting factor to the service life of TKRs remains the wear of the polyethylene tibial liner. Increases in life expectancy and body weight, as well as the trend for TKR surgery in younger patients will put even higher demands on future devices. Preclinical endurance testing has become a standard procedure to predict the mechanical performance of new devices during implant development. These testing procedures follow a test-to-success strategy, which require input data derived from the load and motion spectrum of daily use. However, recent studies show that current international testing standards do not mimic the kinematic and kinetic conditions during gait for patients implanted with a cruciate retaining knee prosthesis. In addition, current protocols focus only on walking, completely omitting other activities of daily living. Although walking is the most frequent activity throughout the day, other daily physicals activities often generate higher tibial loads, larger prosthetic movements, and more detrimental cross-shear than walking. Indeed, wear features of tested components do not match those worn in vivo, neither regarding wear scar size and shape, nor wear morphology. The frontside medial and lateral bearing surfaces of TKRs are not the only surfaces which contribute to wear and osteolysis. Micromotion between the back of the polyethylene liner and the metallic base plate/tray leads to "backside wear". Backside wear has been claimed to be of greater osteolytic significance than the wear experienced on the front articulating surfaces because of the larger backside contact area and the potentially smaller particles generated, although accurate quantification of backside wear has proven difficult. The relationship between daily physical activity and location specific TKR wear is also not known. We hypothesize that the motion and force profiles inputted to wear simulators must be from multiple daily activities measured from TKR patients in order to accurately reproduce clinically observed wear rates and patterns on both the front and backside of TKRs. We propose three aims to investigate our overall hypothesis. In the first two aims we will demonstrate that more realistic wear is generated using input profiles from TKR patients and from multiple daily activities. In the third aim we will design and validate a new multi-activity wear protocol reflecting true in vivo use. We will use novel technology that uses lanthanide stearates to track polyethylene wear in serum with mass spectrometry. Different elements are used for different TKR interfaces to allow in situ tracking of frontside versus backside wear. Findings will be validated using retrievals with unique gait and activity information. The studies are purposefully limited to cruciate-retaining TKR design with a high market share. PUBLIC HEALTH RELEVANCE: A multi-activity simulator standard that will result in wear rates and patterns that closely reflect true in vivo use, unlike current input profiles, will improve the quality of predictive wear tests. This will further advance and speed up the design process of knee prostheses. Any preclinical elimination of material and/or design errors directly improves implant longevity and impacts ultimately the well-being of the patient.